The identification of tumor antigens in melanoma recognized by T cells has heralded a renewed interest in the use antigen-specific immunotherapy for the treatment of malignancies. Vaccine strategies to augment the anti-tumor response in patients are appealing because of their ease of use and potential universal applicability. However, the magnitude and phenotype of the induced response can be unpredictable and limited by in vivo constraints, contributing to difficulties in interpreting the mixed clinical results which have been achieved. Antigen-specific T cell clones of defined specificity and phenotype with a high avidity for tumor cells can be generated in vitro in numbers far greater than that possible by immunization alone. Thus adoptive therapy is a conceptually attractive strategy for manipulating the immune response so that requirements for effective antigen-specific therapy can be established. We have developed methods using genetically engineered and peptide-pulsed APCs to stimulate antigen-specific T cells in the peripheral blood and, peptide-MHC tetramers to rapidly select high avidity tumor-reactive clones. A clinical trial was conducted using adoptively transferred antigen-specific CD8+ T cell clones to evaluate the safety, duration of in vivo persistence and anti-tumor efficacy of infused T cells. This trial demonstrated that adoptive transfer of T cell clones was without significant toxicity and that T cells migrated to sites of disease and mediated an antigen-specific immune response; however, there was limited evidence of clinical regression. Potential obstacles to complete tumor eradication were identified. The in vivo survival of infused CTL was short with a half-life of less than 8 days and tumors developing following T cell infusion demonstrated a selective loss of target antigen expression. Murine models and human studies of adoptive immunotherapy have demonstrated that a form of CD4 help is required to maintain the in vivo survival and function of effector CD8 cells necessary for successful elimination of malignant cells. The outcome of these early clinical results now provides a context for the proposed studies designed to evaluate means to improve the efficacy of antigen-specific adoptive T cell therapy by providing concurrent CD4 T cell helper function through use of low-dose IL-2 and by targeting multiple antigens to overcome the outgrowth of antigen-loss variants as a mechanism of tumor immune escape.